Our overarching goal is to develop a monoclonal antibody-based product for the prevention of seasonal influenza in high risk patients. It is estimated there are 291,243-645,832 deaths annually related to seasonal influenza worldwide. In the United States, the 2017-18 influenza season was classified a high severity season with 79,400 deaths, and 959,000 hospitalizations attributed to influenza, serving as a reminder of the continued severity of influenza and the immense unmet need. At present, the only approved drug for influenza prevention is the influenza vaccine, which is available in multiple seasonally adjusted formulations. Influenza vaccine effectiveness is poor, ranging from 10% to 60%. Monoclonal antibody (mAB) therapeutics are in clinical development, but these are currently focused on treatment indications and not formulated to be practical for influenza prevention. In collaboration with the Crowe laboratory at Vanderbilt University Medical Center, we propose to develop a combination of next generation mAbs that broadly and potently prevents seasonal influenza. The backbone of the combination will be a novel class of fully human anti- influenza mAbs that binds a highly conserved epitope in hemagglutinin (HA) with exceptional potency and breadth and acts through a new mechanism. When used in combination with fully human mAbs against other antigenic sites, this product can deliver a safe and effective vaccine-like product profile. In this STTR Phase I, we will establish the composition of the combination, in vivo efficacy, and developability of lead mAbs, enabling advancement of the optimized lead product in Phase II. To accomplish this, we propose the following Aims: Aim 1. Identify the candidate components for a combination of human anti-influenza mAbs. We will assess diverse anti-influenza mAbs and combinations for breadth and potency to select components to be tested in Aim 2. We have rationally selected mAb combinations to ensure non- competitive binding of epitopes for neutralization testing against a panel of H1 and H3 influenza viruses. Aim 2. Determine in vivo efficacy of anti-influenza mAb candidates and select lead. We will assess in vivo efficacy of 5-8 anti-influenza mAb candidate combinations, pre-selected based on findings of Aim 1. We will perform a series of influenza A (H1N1 and H3N2) escalating dose mouse challenges studies using combinations of mAbs to select a single lead candidate and back-up. Aim 3. Assess manufacturing computational liability and identify candidate siblings with optimized performance and manufacturing computational liability. We will use a commercially available in silico sequence liability assessment platform to perform a multi-parameter assessment of the manufacturability of the lead and back-up candidates from Aim 2. At the end of this Phase I SBIR, we will have established proof-of-concept for our optimized lead anti-influenza mAb combination, and enabled Phase II studies to pursue full preclinical development of this lead.